As rotas de vinho como elementos de desenvolvimento económico

Mestrado em Planeamento do Território - Inovação e Políticas de DesenvolvimentoO sector do turismo em Portugal é responsável pela geração de importantes receitas e pela criação de um número considerável de postos de trabalho. No entanto, existem regiões do país onde a dependência no sector é mais evidente. O sector do turismo assume-se, deste modo, como um factor de alavanca do desenvolvimento socioeconómico e de dinamização e fortalecimento da base económica local, sobretudo devido ao efeito multiplicador económico (directo, indirecto e induzido) e à capacidade de dinamizar e motivar o desenvolvimento de outras actividades económicas. Nesta perspectiva, considera-se necessário adaptar as regiões às tendências e evoluções do mercado do turismo, afirmando os seus valores endógenos e valorizando os elementos diferenciadores e específicos (uniqueness), projectando linhas de desenvolvimento que permitam alavancar o desenvolvimento do Turismo no território, através do aumento de acções de promoção e dos níveis de comercialização que se possam reflectir no aumento do volume de negócios da região associado ao turismo. O enoturismo enquanto produto turístico, não deve restringir-se à existência de unidades vitivinícolas com capacidade para receber visitas. Efectivamente, o produto enoturismo e a sua cadeia de valor, será tanto mais rentável, quanto melhor se valorizar, proteger e promover os recursos endógenos e os atributos diferenciadores da região vitivinícola, integrados num mix de serviços e equipamentos. A organização e qualificação da oferta existente, faculta a possibilidade de captar, em cada local, um maior número de clientes, aproveitando a dinâmica do sector do turismo enquanto sector que origina um fluxo de visitantes (novos potenciais clientes) no território, podendo adquirir directamente os produtos juntos dos produtores, aumentando assim o impacte directo e o volume de negócios de cada agente económico. ABSTRACT: The tourism sector in Portugal is responsible for the generation of significant revenues and the creation of a considerable number of jobs. However, there are regions where the dependence on the tourism sector is more evident. This sector is thus considered as an important element for the socio-economic development and the strengthening of local economies, mainly due to its economic multiplier effect (direct, indirect and induced impacts) and the ability to strengthen and stimulate the development of other economic activities. In this perspective, it is necessary that regions adapt themselves to new trends and developments occurring in the tourism market, avowing their endogenous values and valorising their differentiating and specific elements (uniqueness). In addition, they must set up development policies to enable leveraging the tourism development in the territory, through increased promotion and commercial activities, which would reflect in a better performance in terms of the region’s turnover associated with tourism activities. The wine tourism should not restrict itself to the existence of wine production units that are able to welcome visitors. Undeniably, the wine tourism product and its value chain will be more profitable if the local resources and attributes that differentiate the wine region are better promoted, being integrated in a mix of services and equipments. The organization and qualification of the existing supply provides the ability to attract, at each site, a larger number of customers, exploiting the tourism dynamics. In effect, the tourism sector attracts flows of visitors (potential new customers) into the territory, who may purchase products directly from producers, thus increasing the direct local economic impact and the turnover of each stakeholder

Using routes or itineraries to create networks in regions with low competitiveness

There are territories where the ability of territorial competitiveness can be conditioned by the availability of resources, access, and capacity to attract and retain tourists. The barrier of competitiveness of territories, especially desertified territories with scarce resources, can be overcome through the involvement of all and the integration of stakeholders in a collaborative network. In this sense, with the aim of structuring the offer of tourist routes and itineraries according to the needs of the demand, based on the available resources, it is proposed to structure three models of itineraries according to demand, which can be stated as follows: i) have a reduced cost through a standardized itinerary; ii) be directed towards a group of customers through a segmented itinerary; or iii) make the offer as flexible as possible to meet the specific needs, desires or expectations of a tourist, through a customized itinerary. This paper uses action research to contribute to the improvement of the functioning of routes and itineraries in low-density territories.info:eu-repo/semantics/draf

The genetic architecture of Parkinson's disease : emphasis on genetic susceptibility

Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, following Alzheimer’s disease, and has been commonly designated a sporadic disorder with few environmental triggers. To date, the single most important risk factor for the disease is ageing. Since the proportion of the elderly is growing steadily as the longevity of the population increases, this leads to greater numbers of patients suffering age-associated neurodegenerative diseases, including PD. Parkinson’s disease not only has a devastating effect on the individual patients and their families but it also imposes an enormous socioeconomic burden on society. Nevertheless, about 10% of cases present early-onset of disease, commonly defined at below 40 years of age, and familial clustering, suggesting that genetic factors play a pivotal role in these cases. This led, in the late 1990s, to the identification of mutations that presented clear segregation in families and were, thus, considered pathogenic. Several loci and genes have since been identified where mutations are disease causing, shedding light on the genetic background of mendelian forms of the disease. The work presented herein follows 4 lines of research with the ultimate goal of clarifying the role of genetics in PD. The first chapter was aimed at characterizing mendelian PD in populations where it was mostly unknown. To this end, we have conducted a screening of mendelian genes in a Portuguese cohort, representative of the population of the center region of Portugal. In addition to the Portuguese population, we have also screened a small cohort of samples from sub-Saharian Africa. This was particularly important since it was the first study to address the genetics of PD in a population from this region, where genetic diversity is known to be far greater than in Caucasian Europeans. An approach that has yielded promising results in the past is candidate gene association studies. Broadly, these studies look at common variability in genes that fit the pathogenesis of the disease, and determine if alleles are more frequent in cases when compared to controls. Chapter two deals with two association studies: the first aimed at determining if variants in the gene HFE were associated with PD; while the second was an attempt to replicate recent results implicating the gene GIGYF2 in PD. While the first study was performed only in a Portuguese cohort, the second also looked at an extended cohort from North America. The third chapter builds upon chapter two, still dealing with candidate gene association studies, however, here we looked at a particular gene, where recent results have been very promising. This chapter includes three separate studies: the first performs a standard association study of variants in GBA in the Portuguese cohort. The results from this study prompted us to perform a similar study in different and extended cohorts, which we have done in Study IX using a British cohort. Still in chapter three, we have performed a metaanalysis of association studies of GBA in PD that includes 16 international centers and nearly 11,000 samples. Chapter four deals with a genome-wide association study in PD, where we have tested a very large number of PD cases and controls for markers spread throughout the genome. This approach has the benefit of not making a priori assumptions of genes’ relevance. This is particularly significant when studying a disease like PD where the etiology still remains largely elusive.A Doença de Parkinson (DP) é a segunda doença neurodegenerativa mais frequente, seguindo a Doença de Alzheimer, tendo sido frequentemente designada como uma doença esporádica com potenciais causas ambientais. Até à data, o factor de risco mais relevante para o desenvolvimento da DP é a idade. Uma vez que a proporção da população idosa tem vindo a aumentar, devido ao aumento da longevidade, o número de indivíduos afectados por doenças neurodegenerativas, incluindo DP é, também, cada vez maior. A DP tem, não só um efeito devastador para os indivíduos afectados e suas famílias, mas também um impacto socioeconómico enorme para a sociedade. Apesar da denominação comum de doença esporádica, cerca de 10% de indivíduos com DP apresentam um inicio precoce da doença – definido como início antes dos 40 anos de idade – e indícios de história familiar, sugerindo que factores genéticos desempenham um papel de relevo nestas formas da doença. Este facto esteve na origem, no final da década de 1990, da identificação de mutações que apresentam clara segregação com a doença em algumas famílias, tendo sido, por isso, consideradas mutações patogénicas. Vários genes e localizações cromossómicas foram desde então identificados, nos quais mutações levam invariavelmente ao início da doença, clarificando, em parte, os mecanismos genéticos que estão na base destas formas mendelianas da DP. O trabalho que se segue foi delineado com base em 4 linhas de investigação, com o objectivo final de clarificar o papel dos factores genéticos na DP. O primeiro capitulo deste trabalho teve como objectivo caracterizar formas mendelianas da DP em populações onde este campo não tinha, até a data, sido extensivamente estudado. Com esse fim, levamos a cabo um screening de mutações nos genes mendelianos conhecidos num amostragem da população portuguesa, representativa da população da região Centro. Para além da população Portuguesa, também estudámos uma amostra de origem Subsariana. O estudo deste grupo de indivíduos de origem Africana é de particular importância, uma vez que foi o primeiro trabalho levado a cabo com o objectivo de elucidar a genética da DP numa população daquela região, onde a variabilidade genética é reconhecidamente maior do que na Europa Caucasiana. Um tipo de trabalhos que tem originado resultados promissores até a data são os estudos de associação. Aqui, de uma forma genérica, é estudada a forma como a variabilidade em genes, conhecidos como estando envolvidos na doença, influencia o desenvolvimento da mesma, através da frequência dessas variações em casos e controlos. O segundo capitulo deste trabalho faz uso deste tipo de estudos com dois objectivos: o primeiro prende-se com o gene HFE, verificando se mutações neste gene são factores de risco para a DP; enquanto o segundo objectivo é o de tentar replicar resultados recentes que implicam o gene GIGYF2 na patogénese da DP. Enquanto o primeiro estudo foi realizado apenas numa amostragem da população Portuguesa, o segundo fez uso de uma amostragem adicional de indivíduos Norte Americanos. O terceiro capítulo complementa o capítulo dois, utilizando ainda estudos de associação. No entanto, aqui apenas nos debruçámos sobre um gene em particular (GBA), o qual tem originado resultados muito promissores. Este capítulo inclui três estudos: no primeiro estudo realizamos uma associação entre variantes na GBA na amostragem de indivíduos de origem Portuguesa. Estes resultados levaram-nos a prosseguir o trabalho, desta feita num grupo significativamente maior, de amostras de origem britânica. Ainda no terceiro capitulo realizámos uma meta-análise de estudos de associação da GBA com DP que inclui dados de 16 centros internacionais e cerca de 11,000 amostras. No quarto capitulo realizámos um estudo de associação do genoma completo com a DP. Neste trabalho testámos um numero significativo de marcadores, posicionados ao longo de todo o genoma, em casos e controlos. Este tipo de estudo tem o benefício de não presumir a priori quanto a potencial relevância de genes para a doença. Este facto é de particular importância para uma doença como a DP, onde a etiologia permanece ainda grandemente por explicar.Fundação para a Ciência e Tecnologia e Fundo Social Europeu (SFRH / BD / 29647 / 2006

Mecanismos genéticos e de stresse oxidativo na doença de Parkinson

Mestrado em Métodos Biomoleculares AvançadosA Doença de Parkinson (DP) é a segunda forma de doença neurodegenerativa mais frequente, embora a sua etiologia não seja plenamente conhecida. Durante muitos anos foi considerado que a DP não tinha qualquer componente genética associada, no entanto, no final do século passado, descrições de mutações genéticas que, aparentemente causavam DP, vieram alterar este conceito. Adicionalmente, sabe-se que na área cerebral afectada nos doentes de Parkinson (substância negra e núcleo estriado), há um aumento da agressão causada por espécies reactivas de oxigénio, o que sugeriu um papel do stresse oxidativo na etiologia desta afecção. O objectivo deste trabalho é encontrar marcadores biológicos que permitam um diagnóstico mais precoce e correcto desta doença. Por um lado, pretendemos encontrar alterações genéticas em genes associados à DP, que permitam auxiliar no diagnóstico. Por outro lado, pretendemos verificar se marcadores periféricos de stresse oxidativo se encontram alterados em indivíduos com DP, para que possam ser utilizados no futuro como marcadores de progressão, ou mesmo da própria doença. Para tal, foram estudados cerca de 130 indivíduos com DP e 130 indivíduos controlo sem qualquer sinal de doença neurodegenerativa. Os indivíduos com DP foram seleccionados de forma continua pela equipa clínica dos H. U. C.. Na nossa amostra, representativa da população portuguesa, encontrámos alterações genéticas, conhecidas e não conhecidas, cujos mecanismos são susceptíveis de causar DP. No que diz respeito aos marcadores de stresse oxidativo, encontrámos alterações significativas principalmente no que diz respeito ao ciclo do glutatião, tornando os seus componentes num eventual marcador periférico da DP. Embora as alterações genéticas possam ser consideradas como causa única do desenvolvimento da doença, é possível que existam interacções entre os genes estudados e outros factores. Esta tese evidencia o facto de que a DP é, muito provavelmente, influenciada por factores genéticos e ambientais e, eventualmente, pela interacções entre estes. Embora não tenha sido encontrado um marcador genético, parece evidente que o diagnóstico genético poderá ser, num futuro próximo, uma ferramenta auxiliar de importância extrema no diagnóstico de algumas formas da DP. Por outro lado, o estudo de marcadores de stresse oxidativo, em particular do ciclo do glutatião, podem auxiliar no diagnóstico da DP nesta população. São claramente necessários estudos que determinem a função das proteínas aqui descritas, e que tentem estabelecer uma relação entre os factores aqui apresentados (genéticos e de stresse oxidativo) e factores ambientais, uma vez que, nesta relação poderá estar a resposta para a maioria das questões biológicas colocadas no âmbito da doença de Parkinson.Parkinson's Disease (PD) is the second most common form of neurodegenerative disease, although it's aetiology isn't fully understood. For many years, it was considered that PD had no a genetic backgroud, however, late last century, reports of genetic mutations that apparently were the cause of PD in some families, deeply changed this concept. Furthermore, it is well documented that in the brain region affected in PD patients (substantia nigra and striatum) there's an increase of the aggression caused by reactive oxigen species, what suggested a role for oxidative stress in the aetiology of this disease. In the work presented here, we aim, on one hand, to find genetic alterations in genes reported to be associated with PD, which may be useful in diagnose; and, on the other hand, to determine if peripheral biomarkers of oxidative stress are altered in individuals with this disease, so that they may also be used in the future as an auxiliary tool for diagnosing PD. This study comprised about 130 individuals with PD and 130 healthy controls without any clear sign of neurodegenerative disease. PD patients were selected in a consecutive manner by the clinical team in the University of Coimbra Hospital. There was no other inclusion parameter, although only definite PD patients were included. In our sample, which we consider to be representative of the Portuguese population, we found genetic mutations, some of them known and others unreported so far, that may be responsible for pathogenic mechanisms susceptible to cause the onset of PD. The study of peripheral biomarkers of oxidative stress showed statistical significant differences between PD patients and controls, mainly in the glutathione cycle, making it's components a suitable peripheral marker of PD. Although in some of the cases presented here, genetic mutations may be considered as the only cause of the onset of the disease, it is likely that for the most part of cases, there are interactions between the genes studied and other factors. This work supports the knowledge that PD is, probably, influenced by genetic and environmental factors and, eventually, by interactions between these two. Although we failed to find a suitable genetic marker, it seems clear that genetic diagnose may become, in the near future, an auxilary tool of extreme importance in PD. Furthermore, the study of biomarkers of oxidative stress, mainly glutathione cycle, may be useful in the diagnose of PD in our population. Further research is clearly needed to determine the function of the mutated proteins reported here, and to establish a link between the factors presented here (genetic and oxidative stress) and environmental factors, since it is likely that in this relationship lay most of the answers to all biological questions posed nowadays in PD research

G2019S dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort

LRRK2 mutations have recently been described in families with Parkinson's disease. Here we show that one of them (G2019S) is present in 6% (7 of 124) unrelated cases of disease in a clinic-based sample series from central Portugal, but not present in 126 controls from the same population. Thus, LRRK2 mutations appear to be a common cause of typical Parkinson's disease and as such will alter clinical practice. © 2005 Movement Disorder Societ

Dietary Arthrospira platensis improves systemic antioxidant potential and changes plasma lipids without affecting related hepatic metabolic pathways in post-weaned piglets

Research ArticleBackground: The ability of a high level of dietary Arthrospira platensis, individually or in combination with two exogenous carbohydrate-degrading enzymes (lysozyme and Rovabio®), to improve systemic antioxidant potential and hepatic lipid metabolism was tested in piglets. Forty male post-weaned piglets, sons of Large White × Landrace sows crossed with Pietrain boars, were allocated into 4 groups (n = 10) and fed during 28 days one of the following diets: 1) a control basal diet (cereal and soybean meal); 2) a basal diet with 10% of A. platensis (AP); 3) the AP diet supplemented with 0.005% of Rovabio® (AP + R); 4) the AP diet supplemented with 0.01% of lysozyme (AP + L). Results: Arthrospira platensis decreased BW gain of piglets, regardless the addition of feed enzymes. The majority of plasma metabolites were affected by diets. A. platensis increased total lipids, total cholesterol and LDL-cholesterol, without changing hepatic fatty acid content or modulating, in an expressive manner, the transcriptional profile of lipid sensitive mediators. The antioxidant potential in general, and total carotenoids in particular, were improved by the microalga, regardless lysozyme or Rovabio®. Conclusions: Summing up, A. platensis, individually and combined with feed enzymes, impacts negatively on piglets’ growth but improves the systemic antioxidant potential and changes plasma lipids with a minor modulation on related hepatic metabolic pathwaysinfo:eu-repo/semantics/publishedVersio

Management of Unresectable Localized Pelvic Bone Sarcomas: Current Practice and Future Perspectives

Bone sarcomas (BS) are rare mesenchymal tumors usually located in the extremities and pelvis. While surgical resection is the cornerstone of curative treatment, some locally advanced tumors are deemed unresectable and hence not suitable for curative intent. This is often true for pelvic sarcoma due to anatomic complexity and proximity to vital structures, making treatment options for these tumors generally limited and not unanimous, with decisions being made on an individual basis after multidisciplinary discussion. Several studies have been published in recent years focusing on innovative treatment options for patients with locally advanced sarcoma not amenable to local surgery. The present article reviews the evidence regarding the treatment of patients with locally advanced and unresectable pelvic BS, with the goal of providing an overview of treatment options for the main BS histologic subtypes involving this anatomic area and exploring future therapeutic perspectives. The management of unresectable localized pelvic BS represents a major challenge and is hampered by the lack of comprehensive and standardized guidelines. As such, the optimal treatment needs to be individually tailored, weighing a panoply of patient- and tumor-related factors. Despite the bright prospects raised by novel therapeutic approaches, the role of each treatment option in the therapeutic armamentarium of these patients requires solid clinical evidence before becoming fully established

Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP

Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65years) Alzheimer’s disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early onset AD (mean age at onset of 52.9 years; range 31– 64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d’Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new nonsynonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations

Nitric oxide and prostaglandins -important players in endothelin-1 induced myocardial distensibility Running Title: NO and prostaglandins modulate diastolic ET-1 effects

SUMMARY This study investigated whether endothelin (ET)-1-induced increase in myocardial distensibility is preserved in heart failure (HF) and modulated by nitric oxide (NO) and prostaglandins. New Zealand white rabbits were treated with Doxorubicin (1mg/kg, intravenously twice a weekly for 8 weeks, DOX-HF Group) or saline (Control Group). Effects of ET-1 (0.1, 1, 10nM) were tested in papillary muscles from the DOX-HF group and the Control Group in the presence of: (i) synthase inhibitor), and (iv) Indomethacin (INDO; cyclooxigenase inhibitor). In the presence of an intact EE, ET-1 promoted concentration-dependent positive inotropic and lusitropic effects that were maintained after damaging the EE, in the presence of L-NNA or INDO and in the DOX-HF Group. ET-1 reduced resting tension at the end of the isometric twitch (increased diastolic distensibility) by 3.2±1.3%, 6.0±1.6% and 8.8±2.7% (at 0.1, 1 and 10nM, respectively), in muscles with intact EE, effect that was completely abolished after damaging EE, in the presence of L-NNA or INDO or in the DOX-HF Group. This study demonstrated that the increase in myocardial distensibility induced by ET-1 is absent in HF and is dependent of NO and prostaglandin release

Permanent pacemaker implantation after alcoholic septal ablation induced complete heart block: Long-term impact

Introduction and objectives: Patients with hypertrophic obstructive cardiomyopathy (HOCM) that remain symptomatic despite optimized medical therapy often undergo alcohol septal ablation (ASA). One of the most frequent complications is complete heart block (CHB), requiring a permanent pacemaker (PPM) in variable rates of up to 20% of patients. The long-term impact of PPM implantation in these patients remains unclear. This study aimed to evaluate the long-term clinical outcomes in patients who implant PPM after ASA. Methods: Patients who underwent ASA at a tertiary center were consecutively and prospectively enrolled. Patients with previous PPM or implantable cardio-defibrillator were excluded from this analysis. Patients with and without PPM implantation after ASA were compared based on their baseline characteristics, procedure data and three-year primary endpoint of composite of all-cause mortality and hospitalization and secondary endpoint of composite of all-cause mortality and cardiac cause hospitalization. Results: Between 2009 and 2019, 109 patients underwent ASA, 97 of whom were included in this analysis (68% female, mean age 65.2 years old). 16 patients (16.5%) required PPM implantation for CHB. In these patients, no vascular access, pacemaker pocket or pulmonary parenchyma complications were noted. The baseline characteristics of comorbidities, symptoms, echocardiographic and electrocardiographic findings were identical in the two groups, with higher mean age (70.6±10.0 years vs. 64.1±11.9 years) and lower beta-blocker therapy rate (56% vs. 84%) in the PPM group. Procedure-related data showed higher creatine kinase (CK) peaks in the PPM group (1692 U/L vs. 1243 U/L), with no significant difference in the alcohol dose. At three years after ASA procedure, there were no differences in the primary and secondary endpoints between the two groups. Conclusions: Permanent pacemaker after ASA induced CHB do not affect long term prognosis in hypertrophic obstructive cardiomyopathy patients. Resumo: Introdução e objetivos: Doentes com miocardiopatia hipertrófica obstrutiva (MCHO) sintomáticos apesar de terapêutica médica otimizada são frequentemente submetidos a ablação septal alcoólica (ASA). O bloqueio atrioventricular (BAV) completo é uma complicação frequente, requerendo implantação de pacemaker definitivo em taxas variáveis que podem ir até 20% dos doentes. O impacto a longo prazo da implantação de pacemaker nestes doentes permanente mal-esclarecido. Esta análise pretende avaliar os outcomes clínicos a longo prazo nestes doentes. Métodos: Doentes consecutivos submetidos a ASA num centro terciário foram incluídos e seguidos prospetivamente. Pacientes com pacemaker ou cardiodesfibrilhador prévio foram excluídos desta análise. Os doentes com e sem implantação de pacemaker após a ASA foram caracterizados e comparados relativamente aos endpoints primário (composto de mortalidade e hospitalização por todas as causas) e secundário (composto de mortalidade por todas as causas e hospitalização de causa cardíaca) a três anos. Resultados: Entre 2009 e 2019, 109 pacientes foram submetidos a ASA e 97 foram incluídos nesta análise (68% sexo feminino, idade media 65,2 anos). Implantaram pacemaker 16 doentes (16,5%) após a ASA por BAV completo. Não se registaram complicações vasculares, da loca ou parenquimatosas pulmonares. As características basais foram semelhantes entre os grupos, com maior idade média (70,6 ± 10,0 anos versus 64,1 ± 11,9 anos) e menor taxa de terapêutica beta-bloqueante (56% versus 84%) no grupo de pacemaker. Dados do periprocedimento revelaram maior pico de creatina cinase (CK) no grupo de pacemaker, sem diferença na dose de álcool usado. Aos três anos, os endpoints primário e secundário não mostraram diferenças entre os dois grupos. Conclusão: A implantação de pacemaker definitivo por BAV completo induzido por ablação septal alcoólica não afeta o prognóstico de pacientes com MCHO